Central Acetylcholinesterase Inhibitors Research Articles

Treatment of Anticholinergic Delirium with Oral Rivastigmine: A Case Report

BackgroundAnticholinergic toxicity is commonly encountered in the emergency department. However, the availability of physostigmine, a central acetylcholinesterase inhibitor used to reverse anticholinergic delirium, has been significantly limited due to national drug shortages in the United States. Several articles have explored the viability of rivastigmine as an alternative treatment for these patients. Case ReportA 33-year-old male presented to the emergency department after a suspected suicide attempt. The patient was found with an empty bottle of diphenhydramine at the scene. On arrival, he was tachycardic, delirious, with dilated and nonreactive pupils and dry skin. As the clinical picture was highly suggestive of anticholinergic toxicity, the patient was treated with oral rivastigmine at a starting dose of 4.5mg to reverse his anticholinergic delirium. Though requiring a repeat dose, his delirium resolved without recurrence.Why Should an Emergency Physician Be Aware of This? Oral rivastigmine has been successfully applied here and in other case reports to reverse anticholinergic delirium with the benefit of prolonged agitation control. Emergency physicians may consider this medication in consultation with a specialist, with initial doses starting at 4.5 to 6 mg, if encountering anticholinergic delirium when physostigmine is not available.

Exploring the potential of a novel phenoxyethyl piperidine derivative with cholinesterase inhibitory properties as a treatment for dementia: Insights from STZ animal model of dementia

Alzheimer’s disease (AD) is a neurodegenerative disease, often characterized by progressive deficits in memory and cognitive functions. Cholinesterase inhibitors have been introduced as promising agents to enhance cognition and memory in both human patients and animal models of AD. In the current study, we assessed the effects of a synthetic phenoxyethyl piperidine derivative, compound 7c, as a novel dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), on learning and memory, as well as serum and hippocampal AChE levels in an animal model of AD. The model of dementia was induced by intracerebroventricular injection of streptozotocin (STZ, 2 mg/kg) to male Wistar rats. STZ-treated rats received compound 7c (3, 30, and 300 µg/kg) for five consecutive days. ​Passive avoidance (PA) learning and memory, as well as spatial learning and memory using Morris water maze, were evaluated. The level of AChE was measured in the serum and the left and right hippocampus. Findings demonstrated that compound 7c (300 µg/kg) was able to reverse STZ-induced impairments in PA memory, while also reduced the increased AChE level in the left hippocampus. Taken together, compound 7c appeared to act as a central AChE inhibitor, and its role in alleviating cognitive deficits in the AD animal model suggests that it may have therapeutic potential in AD dementia. Further research is required to assess the effectiveness of compound 7c in more reliable models of AD in light of these preliminary findings.

Gender differences in Parkinson's disease with dementia and dementia with Lewy bodies

BackgroundGender differences for dementia with Lewy bodies (DLB), usually considered an intermediate disease between Alzheimer disease (AD), Parkinson disease (PD), and Parkinson disease with dementia (PDD), is controversial. The present study investigated gender differences in DLB and PDD using demographic and pharmacologic treatment strategies in a retrospective data analysis. MethodData of confirmed cases of DLB and PDD between 2015 and 2020 were collected from the PRISMA dementia data-base registry. Data from 7594 PDD patients and 608 DLB patients were analyzed using logistic regression analysis to determine demographic and pharmacologic factors associated with DLB and PDD patients. ResultIn the adjusted analysis, central acetylcholinesterase inhibitors (ChEIs) including donepezil, galantamine, rivastigmine were associated with DLB. Second generation antipsychotics (SGAs) such as risperidone (odd ratio(OR)=1.900, 95% confidence interval (CI),1.192–3.030, P = 0.007) was associated with females with DLB while aripiprazole (OR=0.195,95% CI,0.06–0.631, P<0.006), and a selective serotonin receptor inhibitor (SSRIs) including escitalopram (OR=0.651, 95% CI,0.468–0.906, P = 0.011), and demographic factors including tobacco use (OR=0.620, 95% CI,0.444–0.866, P<0.005) and increasing age (OR =1.042, 95% CI, 1.025–1.058, P<0.001), were associated with females that present with PDD. Olanzapine (OR=2.871, 95% CI, 1.902–4.334, P<0.001), escitalopram (OR=1.444, 95% CI, 1.079–1.932) and tobacco use (OR=1.424, 95%CI, 1.075–1.887, P = 0.014) were associated with males with DLB. African American males (OR= 0.249, 95% CI, 0.088–0.703, P = 0.009) with a history of ethyl alcohol (ETOH) use (OR= 0.371, 95% CI, 0.260–0.531, P<0.001) treated with aripiprazole (OR=0.581, 95%CI, (0.302–1.118), P = 0.004) were associated with PDD. ConclusionOur findings reveal similarities and differences in demographic and pharmacologic factors associated with DLB and PDD. Investigating the effect of identified factors on DLB or PDD in future studies can help improve the care of DLB and PDD patients.

Enhanced parasympathetic cholinergic activity with galantamine inhibited lipid-induced oxidative stress in obese African Americans

BackgroundAfrican Americans (AAs) are disproportionately affected by cardiovascular disease (CVD), they are 20% more likely to die from CVD than whites, chronic exposure to inflammation and oxidative stress contributes to CVD. In previous studies, enhancing parasympathetic cholinergic activity has been shown to decrease inflammation. Considering that AAs have decreased parasympathetic activity compared to whites, we hypothesize that stimulating it with a central acetylcholinesterase (AChE) inhibitor, galantamine, would prevent lipid-induced oxidative stress.ObjectiveTo test the hypothesis that acute dose of galantamine, an AChE inhibitor, decreases lipid-induced oxidative stress in obese AAs.MethodsProof-of-concept, double-blind, randomized, placebo-controlled, crossover study that tested the effect of a single dose of 16 mg of galantamine versus placebo on lipid-induced oxidative stress in obese AAs. Subjects were studied on two separate days, one week apart. In each study day, 16 mg or matching placebo was administered before 20% intralipids infusion at doses of 0.8 mL/m2/min with heparin at doses of 200 U/h for 4 h. Outcomes were assessed at baseline, 2 and 4 h during the infusion.Main outcome measuresChanges in F2-isoprostane (F2-IsoPs), marker of oxidative stress, measured in peripheral blood mononuclear cells (PBMC) and in plasma at baseline, 2, and 4-h post-lipid infusion. Secondary outcomes include changes in inflammatory cytokines (IL-6, TNF alpha).ResultsA total of 32 obese AA women were screened and fourteen completed the study (age 37.8 ± 10.70 years old, BMI 38.7 ± 3.40 kg/m2). Compared to placebo, 16 mg of galantamine significantly inhibited the increase in F2-IsoPs in PBMC (0.007 ± 0.008 vs. − 0.002 ± 0.006 ng/sample, P = 0.016), and plasma (0.01 ± 0.02 vs. − 0.003 ± 0.01 ng/mL, P = 0.023). Galantamine also decreased IL-6 (11.4 ± 18.45 vs. 7.7 ± 15.10 pg/mL, P = 0.021) and TNFα levels (18.6 ± 16.33 vs. 12.9 ± 6.16 pg/mL, P = 0.021, 4-h post lipid infusion) compared with placebo. These changes were associated with an increased plasma acetylcholine levels induced by galantamine (50.5 ± 10.49 vs. 43.6 ± 13.38 during placebo pg/uL, P = 0.025).ConclusionsIn this pilot, proof-of-concept study, enhancing parasympathetic nervous system (PNS) cholinergic activity with galantamine inhibited lipid-induced oxidative stress and inflammation induced by lipid infusion in obese AAs.Trial registration: ClinicalTrials.gov identifiers NCT02365285.

Десять принципов применения ингибиторов холинэстеразы для лечения деменции в клинической практике

Central acetylcholinesterase (AChE) inhibitors belong to the basic drugs for the treatment of dementia. The article discusses the basic principles of AChE in clinical practice. Particular attention is paid to the measures of evaluation concerning the efficacy of drugs (given the properly titrated dose), to the improvement of drug tolerability, in particular, through the prescription of correctors (drugs that reduce the severity of AChE adverse events), and a balanced approach to the AChE prescription, given the absolute and relative contraindications and polypragmasia characteristic of elderly patients with dementia. The article also emphasizes the importance of informing relatives and caregivers about the AChE mechanism of action to form an adequate level of expectations and rational use of pharmacotherapy. The article lists the situations in which the AChE cancellation is justified even if there is a therapy effect. KEYWORDS: dementia, Alzheimer’s disease, cognitive impairment, basic therapy, cholinesterase inhibitors, dose titration, donepezil. FOR CITATION: Chebotareva A.D., Levin O.S. Ten principles of using the cholinesterase inhibitors in the treatment of dementia in clinical practice. Russian Medical Inquiry. 2022;6(10):576–579 (in Russ.). DOI: 10.32364/2587-6821-2022-6-10-576-579.

A Rare Situation in Childhood: Anticholinergic Syndrome Due to Biperiden Intoxication

Biperiden is an anticholinergic agent that acts on the central nervous system. It is used in the treatment of Parkinsonism and extrapyramidal symptoms. Anticholinergic syndrome develops in biperiden poisoning. Physostigmine is an effective central acetylcholinesterase inhibitor. In this article, we aimed to share our experience of using physostigmine in a case of central anticholinergic syndrome developing due to biperidene poisoning in a 4-year-old girl.

Cognitive impairment in hypertension

As the life expectancy of the population increases, cognitive impairment (CI) caused by cerebrovascular diseases is becoming an increasingly urgent problem. The leading role of hypertension in the development of CI of various origins has led to intense discussions about blood pressure control as a potential therapeutic strategy for achieving optimal brain perfusion and about the prevention of mild and moderate CI. Hypertension is the main modifiable risk factor for stroke and cerebral small vessel damage that results in nonstroke-related CI. Antihypertensive therapy plays an essential role in preventing the development and slowing down the progression of CI through blood pressure control. Neurometabolic and neuroprotective drugs (Vinpotropil ® , Cholitilin ® ) are actively used to treat CI that does not reach the degree of dementia. When dementia develops, reversible NMDA receptor inhibitors (memantine) and central acetylcholinesterase inhibitors are used to correct CI.

Approach to Cognitive Impairment in Parkinson's Disease.

Cognitive dysfunction is common in Parkinson's disease (PD) and predicts poor clinical outcomes. It is associated primarily with pathologic involvement of basal forebrain cholinergic and prefrontal dopaminergic systems. Impairments in executive functions, attention, and visuospatial abilities are its hallmark features with eventual involvement of memory and other domains. Subtle symptoms in the premotor and early phases of PD progress to mild cognitive impairment (MCI) which may be present at the time of diagnosis. Eventually, a large majority of PD patients develop dementia with advancing age and longer disease duration, which is usually accompanied by immobility, hallucinations/psychosis, and dysautonomia. Dopaminergic medications and deep brain stimulation help motor dysfunction, but may have potential cognitive side effects. Central acetylcholinesterase inhibitors, and possibly memantine, provide modest and temporary symptomatic relief for dementia, although there is no evidence-based treatment for MCI. There is no proven disease-modifying treatment for cognitive impairment in PD. The symptomatic and disease-modifying role of physical exercise, cognitive training, and neuromodulation on cognitive impairment in PD is under investigation. Multidisciplinary approaches to cognitive impairment with effective treatment of comorbidities, proper rehabilitation, and maintenance of good support systems in addition to pharmaceutical treatment may improve the quality of life of the patients and caregivers.

Combination and mutual effect of Alzheimer’s disease and cerebrovascular disease

Alzheimer’s disease (AD), cerebrovascular disease and their combination are the most common causes of cognitive impairment (CI) and therefore disability in senior citizens. Mutual influences, manifestations and diagnostics of AD and vascular CI are analyzed. The presence of a vascular component in the development of CI indicates the possibility of their prevention. Treatment of CI is based on correction of vascular factors, non-drug and drug methods to improve cognitive functions. Psychosocial and behavioral methods, cognitive training, central acetylcholinesterase inhibitors and memantine are effective in dementia. The use of cerebrolysine in AD and vascular CI is discussed.

Abstract P154: Central Acetylcholinesterase Inhibitor, Galantamine, Prevents Lipid-Induced Oxidative Stress in African Americans

African American women (AAW) have one of the highest prevalence of hypertension in the US. Obese AAW have decreased parasympathetic (PNS) activity compared to white women (WW). Continuous lipid infusion that causes cardiovascular autonomic imbalance (decrease in PNS and increase in sympathetic activity) induces a greater increase in oxidative stress in African Americans than in whites. Considering that PNS protects against oxidation and that central acetylcholinesterase inhibitors have been shown to suppress oxidative stress in animal models; we tested the hypothesis that the central acetylcholinesterase inhibitor, galantamine attenuates oxidation in response to lipid infusion in obese AAW compared to WW. We randomized 14 healthy obese AAW (39.5±10.7 yo, BMI 38.8±3.4) and 10 WW (35.9±8.3 yo, BMI 36.3±2.1). All subjects underwent 4-h infusions of Intralipids and heparin. On separate days subjects received either 16 mg galantamine or placebo in a crossover fashion. Lipid-induced oxidative stress and inflammation were assessed with plasma F2-isoprostanes and cytokines at baseline, 2 and 4-h post-intralipid infusion. In AAW, 16 mg of galantamine significantly suppressed the increase in lipid-induced oxidative stress (-3±12 vs. 10±18 pg/mL with placebo, P=0.014), figure . No effect was noted in WW. Galantamine tended to increase IL10 levels (17.3±20.7 vs. 4.8±7.58 pg/mL, P=0.06). We did not observe any effect on blood pressure or heart rate. Conclusion: Increased parasympathetic tone with central acetylcholinesterase inhibitor, galantamine, suppressed lipid-induced oxidative stress in obese African American women.

Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a "Bio-Oxidizable" Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation.

With the aim of reducing side effects of acetylcholinesterase inhibitors (AChEIs) during symptomatic treatment of Alzheimer's disease, we report herein a new class of donepezil-based "bio-oxidizable" prodrugs 1 designed to be converted into dual binding site AChEIs 2. While most of indanone-derived N-benzylpyridinium salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines 1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high in vitro antioxidant activity, its conversion to AChEI 2r could be easily achieved under mild conditions when incubated in various oxidizing media. Lastly, both compounds 1r and 2r did not show genotoxicity in vitro and displayed high LD50 values in mice, making this prodrug 1r/drug 2r couple a good candidate for further in vivo biological experiments.

Galantamine protects against lipopolysaccharide-induced acute lung injury in rats.

Lipopolysaccharide (LPS)-induced endotoxemia triggers the secretion of proinflammatory cytokines and can cause acute lung injury (ALI). The high mobility group box 1 (HMGB1) protein plays an important role as a late mediator of sepsis and ALI. Galantamine (GAL) is a central acetylcholinesterase inhibitor that inhibits the expression of HMGB1. This study evaluated the effects of GAL by measuring levels of inflammatory mediators and observing histopathological features associated with LPS-induced ALI. Sixty 8-10 week old male Sprague-Dawley rats (200-240 g) were randomized into three groups as follows: control group, LPS group (7.5 mg/kg LPS), and LPS+GAL group (5 mg/kg GAL before LPS administration). Histopathological examination of lung specimens obtained 12 h after LPS administration was performed to analyze changes in wet-to-dry (W/D) weight ratio, myeloperoxidase (MPO) activity, and HMGB1 expression level. Additionally, plasma concentrations of tumor necrosis factor-α, interleukin-6, and HMGB1 were measured using an enzyme-linked immunosorbent assay at 0 (baseline), 3, 6, 9, and 12 h after LPS administration. Mortality in the three groups was recorded at 72 h. LPS-induced ALI was characterized by distortion of pulmonary architecture and elevation of MPO activity, W/D weight ratio, and levels of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, and HMGB1. Pretreatment with GAL significantly reduced the LPS-induced lung pathological changes, W/D weight ratio, levels of pro-inflammatory cytokines and MPO activity (ANOVA). Moreover, GAL treatment significantly decreased the mortality rate (ANOVA). In conclusion, we demonstrated that GAL exerted a protective effect on LPS-induced ALI in rats.

A novel therapeutic intervention for postencephalitic mental retardation

Viral encephalitis is often followed by cognitive sequelae including intellectual decline whose pathophysiology remains obscure till date. Based on recent laboratory studies implicating the cholinergic system in viral encephalitis, the authors postulate the hypothesis that cholinergic deficit might account for some of the cognitive sequelae in at least some types of viral encephalitis, which might be benefited by central acetyl cholinesterase inhibitors. The case of an adolescent with postencephalitic intellectual decline responding robustly to donepezil is presented.

Current therapy for chronic cerebrovascular attack

Chronic cerebrovascular attack (CCVA) is a brain lesion caused by vascular factors. CCVA appears as cognitive impairments (CIs), affective (emotional) disorders and focal syndromes. Treatment for CCVA requires a comprehensive approach. Effective combination therapy for CCVA involves secondary prevention of stroke and CIs; treatment of CIs; treatment of depression and other affective disorders; and neuroprotective therapy. Basic therapy for CCVA includes modification of risk factors, antihypertensive, hypolipidemic, and antithrombotic therapies. Central acetylcholinesterase inhibitors (galantamine, rivastigmine, donepezil) and a reversible NMDA receptor blocker (memantine) are symptomatically used at a stage of vascular and mixed dementia. There are no unique guidelines for the therapy of mild and moderate vascular nondementia-related CIs. Drug use, based on the neurochemical mechanisms underlying the development of vascular CIs, is substantiated. When choosing psychotropic agents, it is necessary to take into account the causes and clinical manifestations of neuromediator deficiency. Antidepressants are used as essential drugs. Neuroleptics and tranquilizers are additionally administered in complex-pattern syndromes, such as depression with marked anxiety. Prescription of neuroprotectors may be effective in treating both stroke and CCVA. These medicaments are most effective when a damaging factor acts, i.e. neuroprotectors should be given in a risk situation and to reduce damage. Citicoline is one of the most test drugs in a group of neuroprotectors.

Management of patients with post-stroke dementia

Dementia occurs in 10-20% of cases and substantially hampers the rehabilitation of patients who have had stroke. Management of patients with post-stroke dementia is based on the prevention of recurrent stroke, cognitive stimulation, and the use of drugs improving cognitive functions. The paper gives the data available in the literature on the results of randomized placebo-controlled trials evaluating the efficacy of central acetylcholinesterase inhibitors and the NMDA receptor antagonist akatinol memantine in vascular dementia, as well as the author’s positive experience with akatinol memantine used in 20 patients.

Stress-induced altered cholinergic–glutamatergic interactions in the mouse hippocampus

Psychological stress may lead to long-lasting brain dysfunction, specifically altered emotional and cognitive capabilities. Previous studies have demonstrated persistent changes in the expression of key cholinergic genes in the neocortex and hippocampus following stress with muscarinic receptor-mediated enhanced excitability. In the present study we examined cholinergic-mediated glutamatergic transmission in the hippocampus of mice after exposure to stress and its potential role in synaptic plasticity and altered behavior. Adult male mice were tested one month after repeated forced swimming test. Non-treated age-matched animals served as controls. Electrophysiological recordings were performed in the acute in-vitro slice preparation. CA1 pyramidal neurons were recorded using whole cell patch configuration. Extracellular recordings were done in response to Shaffer collaterals (SC) or stratum orien (SO) stimulation. Animal behavior in response to inhibition of acetylcholinesterase (AChE) was tested in open field paradigms. In whole cell patch recordings the frequency of excitatory post-synaptic currents (EPSCs) was significantly increased in response to muscarinic activation in stress-exposed animals. This enhanced cholinergic-modulated excitatory transmission is associated with facilitation of long-term potentiation (LTP) in response to tetanic stimulation at the SO but not at the SC. Stress-related behavioral modulation via central cholinergic pathways was enhanced by the central AChE inhibitor, physostigmine, thus further supporting the notion that stress is associated with long lasting hypersensitivity to acetylcholine. Our results revealed a pathway-specific enhancement of cholinergic-dependent glutamatergic transmission in the hippocampus after stress. These changes may underlie specific hippocampal malfunction, including cognitive and emotional disturbances, as observed in patients with post-traumatic stress disorder (PTSD).

HOW TO MANAGE OVERACTIVE BLADDER IN ELDERLY INDIVIDUALS WITH DEMENTIA? A COMBINED USE OF DONEPEZIL, A CENTRAL ACETYLCHOLINESTERASE INHIBITOR, AND PROPIVERINE, A PERIPHERAL MUSCARINE RECEPTOR ANTAGONIST

HOW TO MANAGE OVERACTIVE BLADDER IN ELDERLY INDIVIDUALS WITH DEMENTIA? A COMBINED USE OF DONEPEZIL, A CENTRAL ACETYLCHOLINESTERASE INHIBITOR, AND PROPIVERINE, A PERIPHERAL MUSCARINE RECEPTOR ANTAGONIST

Donepezil in traumatic brain injury: Report of two cases

Adults with traumatic brain injury (TBI) are often severely impaired and inadequately rehabilitated due to deficits in memory and behavioral problems like apathy, irritability and depression, and it has been suggested that an acetylcholine deficit could be contributory to these deficits. Central Acetyl cholinesterase Inhibitors (CAI) are being reported to have a beneficial impact in treatment of memory deficits in adults with TBI, with Donepezil studied most extensively. The authors present two patients with TBI with long term static dysfunction of memory and behavior who responded to Donepezil in terms of attention, memory and apathy. Donepezil appears to be a valuable pharmacological option for treatment of memory and behavioral deficits in TBI.

CIMT as a behavioral engine in research on physiological adjuvants to neurorehabilitation: The challenge of merging animal and human research

A physiological adjuvant to neuroplasticity cannot put new knowledge into the brain - it can only augment behavioral rehabilitation, which does replace knowledge in the brain lost due to injury. Clinical trials of adjuvant agents should therefore incorporate behavioral engines: behavioral therapies that have a potent effect and minimize error variance due to variability in subject attributes and the administration of the therapy. We consider in some detail the attributes of behavioral engines with a particular focus on constraint induced movement therapy. Human trials of physiological adjuvants to neuroplasticity are predicated on discoveries from animal research. Because human trials are expensive and carry risk of injury, it behooves us to lay a comprehensive foundation for these trials with animal studies (also incorporating behavioral engines) and to carefully mesh animal and clinical work. We review in detail our own and others' work involving human subjects with brain lesions and animal models of brain injury using donepezil, a central acetyl cholinesterase inhibitor, d-cycloserine, a partial agonist at the NMDA receptor glycine site, d-amphetamine, and methylphenidate in an effort to elucidate the strengths and weakness of animal and human neurorehabilitation science with respect to this mesh between animal and human subject research. We consider modifications in current approaches that might more efficiently advance neurorehabilitation science.

Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury—clinical experience in 111 patients

Purpose Theoretically, central acetylcholinesterase inhibitors (CAIs) could alleviate at least some of the main symptoms of chronic traumatic brain injury (TBI). The aim of this report is to describe clinical experience of the treatment of chronic TBI with these drugs. General methods From an outpatient clinic material, 111 patients were selected having chronic stable TBI with at least one of the following target symptoms: fatigue, poor memory, diminished attention or diminished initiation. Patients received in random donepezil, galantamine or rivastigmine. The evaluation of the treatment response was based on the subjective view of the patient. Findings As first treatment, 27 patients received donepezil, 30 galantamine and 54 rivastigmine. Altogether 41 patients tried more than one drug, but only three patients tried all three alternatives. In total, 61% of patients had a marked positive response and 39% a modest or no response. The clearest effect was in almost all responders a better vigilance and attention causing better general function. About half of the patients (55%) wanted to continue therapy with one of these drugs. The therapeutic response became very quickly and at low doses. There were no significant differences between the three drugs either in effect or tolerability. The age, sex, type of injury, severity of TBI or elapsed time after injury did not affect the response. The mean dose in maintenance therapy was 7.2 mg od for donepezil, 5.0 mg bid for galantamine and 2.3 mg bid for rivastigmine. Side effects or inadequate therapeutic response were the main causes for discontinuation with nearly equal frequency. Paradoxical responses were seen in some patients. Conclusions CAIs show a very promising therapeutic potential in the treatment of chronic TBI. There were no significant differences between the three drugs. Large-scale randomised double-blinded placebo-controlled studies are clearly needed.